Abstract
Objective: To investigate the correlation between the vitamin A, D, and E levels and recurrent respiratory tract infections (RRTIs) in children of different ages. Methods: A total of 150 RRTI patients were divided into three groups: the 0 to 2 year-old group, the 3-5 year-old group, and the 6-14 year-old group. Collectively, we refer to the three groups as the RRTI group. The serum vitamin A, D and E levels were measured in the three groups. Healthy children without RRTIs were recruited as a control group. The correlations between the changes in the vitamin A, D, and E levels and the RRTIs were analyzed. Results: The vitamin A, D, and E levels decreased significantly in the children with RRTIs, but only the vitamin A and D levels were negatively correlated with the incidence of RRTIs, while the vitamin E levels were not significantly correlated with the incidence of RRTIs. The follow-up results showed that the serum vitamin A, D, and E levels in the RRTI group were significantly increased after the treatment, and the WBC and CRP levels were remarkably reduced. Conclusion: Monitoring the serum vitamin A and D levels helps determine the disease severity, and the supplementation of adequate vitamin A and D through diet or drugs is of great help in treating RRTIs.
Keywords: Vitamins, recurrent respiratory tract infections (RRTIs), disease severity, children
Introduction
Recurrent respiratory tract infections (RRTIs) are upper and lower respiratory tract infections that frequently occur within a period of one year, a frequency far beyond the normal range [1-3]. Upper respiratory tract infection is a general term for a group of diseases, including laryngitis, pharyngitis-tonsillitis, viral pharyngitis, and the common cold, over 90% of which are caused by viruses. Lower respiratory tract infection refers to infections that develop below the throat, including various tracheitis, pneumonia, bronchiectasis, etc., which are attributable to downward infections of pathogenic bacteria from upper respiratory tract infections [4-7]. RRTIs are common diseases in children, and the incidence of RRTIs has been increasing in recent years due to deterioration caused by environmental pollution. Repeated attacks are likely to happen, resulting in complications such as myocarditis, sepsis, nephritis, etc. [8-11]. Hospitalized children and those with low body immunity are susceptible to this disease, indicating that there is a certain correlation between the child’s immune system and the occurrence of the disease. Studies have shown that vitamins A, D, and E can enhance immunity, but studies that explore the correlation between the levels of vitamins A, D, and E in children and the occurrence of clinical RRTIs are rarely seen. In this study, a total of 150 children with respiratory tract infections from different age groups were recruited as the study cohort, and, as the same time, 120 healthy children were recruited as the control group, aiming to explore the correlation between vitamins A, D, and E and children with different respiratory tract infections.
Methods
The study cohorts
A total of 150 children suffering from RRTIs treated in our hospital from August 2017 to May 2019 ranging in age from 0-14 years, old and who volunteered to participate in our study were divided into the 0-2 year-old group, the 3-5 year-old group, and the 6-14 year-old group, with the three groups collectively called the RRTI group. At the same time, 120 healthy children of the same ages were recruited as the control group. The diagnostic criteria of children’s RRTIs were as follows: the frequencies of the upper and lower respiratory tract infections for the 0-2 year-olds were 7 times and 3 times respectively; for the 3-5 year-olds they were 6 times and 2 times respectively; for the 6-14 year-olds they were 5 times and 2 times respectively. This study was approved by the Ethics Committee of Cangzhou Central Hospital. All the involved patients signed the informed consent forms.
Measuring the serum vitamin A, D, and E levels
About 2 mL of peripheral venous blood was drawn from each child according to the principle of aseptic operation, and the samples were stored in a biochemical tube protected from light. The blood was centrifuged at 4000 r/min for 10 minutes, and the supernatant was drawn into a clean EP tube to determination the serum vitamin A, D, and E levels. We used high-performance liquid chromatography (HPLC) measurement technology to determine the serum vitamin A, D, and E levels. The measurement instrument was a high-performance liquid chromatograph (German Keysys automatic biochemical analyzer), and the procedure was performed as required by the specifications of the kit.
Treatment methods
The RRTI group was given 2,500 U of vitamin A soft capsules each time, orally, once every other day in addition to the standard treatments such as anti-infection and atomization, vitamin D drops 400 U each time, orally, once every other day, and vitamin E capsules 2.5 mg each time, orally, once every other day. All the patients in the study were followed up for 1 year, and those who withdrew from the study during the follow-up period were excluded. The vitamin A, D, and E levels and the infection indicators of the children in the RRTIs group were counted and compared before and after the treatment [white blood cell count (WBC) and c-reactive protein (CRP)].
Statistical methods
SPSS 21.0 statistical software was used for statistical analysis. The measurement data were expressed as the mean ± standard deviation (x ± s). Independent sample t-tests were used for the comparisons between groups, the comparisons within a group were conducted using t tests. ANOVA was used for the comparison between multiple groups, and Pearson correlation coefficients were performed for the correlation analysis. The graphics were mapped using GraphPad Prism 8. P < 0.05 was considered statistically significant.
Results
General information
According to the inclusion criteria, a total of 150 children (0-14 years old) with RRTIs and 120 healthy children (0-14 years old) were enrolled. There were no significant differences in the general information between each age group in terms of age, weight, or height (P > 0.05, Table 1).
Table 1.
The general information of the children of different ages
| Age (months) | Body weight (kg) | Height (cm) | |
|---|---|---|---|
| Control group (0-2 years) | 18.05 ± 3.44 | 12.89 ± 2.23 | 83.90 ± 4.51 |
| RRTI group (0-2 years) | 18.48 ± 4.36 | 12.20 ± 2.59 | 84.08 ± 4.99 |
| t value | 8.421 | 7.456 | 6.529 |
| P value | 0.249 | 0.5495 | 0.775 |
| Control group (3-5 years) | 58.55 ± 10.23 | 18.19 ± 9.13 | 108.90 ± 24.51 |
| RRTI group (3-5 years) | 58.48 ± 10.16 | 19.70 ± 10.15 | 110.08 ± 33.99 |
| t value | 7.441 | 6.522 | 7.328 |
| P value | 0.419 | 0.435 | 0.687 |
| Control group (6-14 years) | 108.55 ± 30.44 | 28.09 ± 12.23 | 139.90 ± 29.15 |
| RRTI group (6-14 years) | 111.48 ± 40.36 | 29.01 ± 12.59 | 141.08 ± 30.09 |
| t value | 9.378 | 5.751 | 7.663 |
| P value | 0.599 | 0.675 | 0.597 |
The proportions of the upper and lower respiratory tract infections in the children of different ages
The proportion of upper respiratory tract infections in the children aged 0-2, 3-5, and 6-14 years old accounted for 73.69%, 71.0%, and 68.90%, while the proportions of lower respiratory tract infections accounted for 26.31%, 29.00%, and 31.10%.
The rates of vitamin deficiency measured in the children of different ages
We calculated the measurement rates of vitamins A, D, and E among the 150 children of all ages (Table 2). The rates of vitamin A deficiency measured in the 0-2, 3-5, and 6-14 year-old groups were 69.80%, 71.00%, and 68.90%, respectively, demonstrating that vitamin A deficiency is common in children. The rates of vitamin D and E deficiency in the 0-2, 3-5, and 6-14 year-old groups were 16.70%, 10.90%, and 26.80% and 2.48%, 1.79%, and 2.69%, respectively, indicating that vitamin D and E deficiency are relatively rare among children.
Table 2.
The vitamin deficiency rates in the children of different ages
| Index | 0-2 years | 3-5 years | 6-14 years |
|---|---|---|---|
| The prevalence of Vitamin A deficiency | 69.80% | 71.00% | 68.90% |
| The prevalence of Vitamin D deficiency | 16.70% | 10.90% | 26.80% |
| The prevalence of Vitamin E deficiency | 2.48% | 1.79% | 2.69% |
The three groups’ vitamin A levels
We tested the serum vitamin A levels in the children of different ages. In the healthy children aged 0-2, 3-5, and 6-14, the serum vitamin A levels were (0.5467 ± 0.07251), (0.6721 ± 0.0798), and (0.6692 ± 0.08912) respectively, which were within the normal range (Table 3). In the RRTI children, the vitamin A levels were (0.3553 ± 0.09777), (0.3627 ± 0.06069), and (0.3241 ± 0.06252), respectively. By comparison, it was found that the vitamin A level in the RRTI children was significantly lower than of the vitamin A level in the normal children of the same age (P < 0.05), suggesting that the vitamin A level has a certain correlation with the incidence of RRTIs.
Table 3.
Vitamin A, D, and E level in the children with different ages
| Years | Group | Vitamin A level (mg/L) | Vitamin D level (mg/L) | Vitamin E level (mg/L) |
|---|---|---|---|---|
| 0-2 years | Control group | 0.5467 ± 0.07251 | 60.28 ± 21.89 | 19.28 ± 5.77 |
| RRTIs group | 0.3553 ± 0.09777 | 11.91 ± 2.65 | 16.07 ± 3.47 | |
| t | 6.412 | 28.739 | 7.845 | |
| P | < 0.001 | < 0.001 | 0.873 | |
| 3-5 years | Control group | 0.6721 ± 0.0798 | 62.89 ± 18.79 | 18.92 ± 4.77 |
| RRTIs group | 0.3627 ± 0.06069 | 12.70 ± 5.99 | 15.52 ± 2.64 | |
| t | 5.574 | 27.352 | 6.587 | |
| P | < 0.001 | < 0.001 | 0.535 | |
| 6-14 years | Control group | 0.6692 ± 0.08912 | 65.99 ± 21.72 | 17.92 ± 4.28 |
| RRTIs group | 0.3241 ± 0.06252 | 26.63 ± 7.22 | 14.29 ± 2.18 | |
| t | 5.541 | 24.451 | 7.378 | |
| P | < 0.001 | < 0.001 | 0.749 |
The three groups’ vitamin D levels
As shown in Table 3, the serum vitamin D levels in the healthy children and the RRTI children 0-2 years old, 3-5 years old, and 6-14 years old were (60.28 ± 21.89), (62.89 ± 18.79), and (65.99 ± 21.72) and (11.91 ± 12.65), (12.70 ± 5.988), and (26.63 ± 7.219). The data analysis showed that the vitamin D levels in the RRTIs group were significantly lower than the vitamin D levels in the healthy children of the same age (P < 0.05), showing that the vitamin D level has a certain correlation with the incidence of RRTIs.
The three groups’ vitamin E levels
Subsequently, we measured the serum vitamin E levels of the children of different ages. The serum vitamin E levels of the healthy children of different ages and the children with RRTIs were maintained at around 16 mg/L (Table 3). There was no significant difference in the vitamin E levels between the healthy group and the RRTI children (P > 0.05), revealing that the serum vitamin E level may be related to RRTIs.
Correlation analysis between the vitamin A, D, and E levels of the three groups and RRTIs
The correlation analysis found that the vitamin A and D levels in the children aged 0-2, 3-5, and 6-14 years were significantly correlated with the incidence of RRTIs (Table 4). The correlation coefficients between the vitamin A levels and the incidence of RRTIs in the children aged 0-2, 3-5, and 6-14 years were -0.601, -0.654, and -0.598, respectively. The correlation coefficients between the vitamin D levels and the incidence of the RRTIs were -0.662, -0.683, -0.601 (P < 0.05). The correlation coefficients between vitamin E in the serum of the children of different age groups and the incidence of RRTIs were -0.189, -0.098, -0.124 (P > 0.05), demonstrating that the vitamin A and D levels have a significant correlation with the incidence of RRTIs.
Table 4.
Correlation analysis
| Vitamin A level | Vitamin D level | Vitamin E level | ||||
|---|---|---|---|---|---|---|
|
|
|
|
||||
| r value | P value | r value | P value | r value | P value | |
| RRTIs group (0-2 years) | -0.601 | 0.0129 | -0.662 | 0.0098 | -0.189 | 0.501 |
| RRTIs group (3-5 years) | -0.654 | 0.0098 | -0.683 | 0.0191 | -0.098 | 0.612 |
| RRTIs group (6-14 years) | -0.598 | 0.0101 | -0.601 | 0.0112 | -0.124 | 0.721 |
Follow-up results
All the children with RRTIs were followed up. The serum vitamin A, D, and E levels were significantly increased after the treatment in the RRTIs group, and their WBC and CRP levels were significantly reduced (P < 0.05), Table 5.
Table 5.
Comparison of the serum vitamin A, D, and E and the infection index levels before and after treatment in the RRTI group (x ± s)
| Time | Vitamin A level (mg/L) | Vitamin D level (mg/L) | Vitamin E level (mg/L) | WBC (109) | CRP (mg/L) |
|---|---|---|---|---|---|
| before treatment | 0.35 ± 0.02 | 17.07 ± 3.44 | 15.29 ± 2.33 | 13.77 ± 4.74 | 11.95 ± 6.71 |
| after treatment | 0.63 ± 0.06 | 63.05 ± 19.79 | 18.71 ± 7.88 | 10.89 ± 4.54 | 8.77 ± 6.53 |
| t | 8.800 | 2.530 | 5.097 | 5.374 | 4.160 |
| P | < 0.001 | < 0.001 | < 0.001 | < 0.001 | < 0.001 |
Discussion
Respiratory tract infections are common in children and occur more often in spring and winter. In developing countries, 20% of children die from respiratory infections, especially lower respiratory infections and pneumonia. Respiratory tract infection is a general term involving a large class of diseases, and such infections can also trigger some complications, such as myocarditis, sepsis, nephritis, etc. [12-15]. Improving children’s own immunity can enhance the resistance to these respiratory infections. Vitamins play vital roles in boosting immunity in children and even adults, but few studies have reported a correlation between vitamin levels in children and RRTIs. This study analyzed children of different ages and explored the correlations between the vitamin A, D, and E levels in children of different ages and RRTIs.
The ciliated epithelial tissue in the respiratory tract can form a protective barrier for the respiratory tract, but it is not fully developed in children, and the expression of related receptors (such as toll receptors) in the epithelial tissue is low, and the resistance to pathogens is rather low, so respiratory infections are likely to occur. Vitamin A cannot only maintain the growth of cell functions and the integrity of the epithelium, but it can also stimulate the body cells to produce certain cytokines, thereby promoting the production of antibodies by B cells. Therefore, vitamin A deficiency can cause respiratory tract mucosal epithelial squamous metaplasia, cortical keratinization, epithelial shedding, and decreased mucus secretion. In particular after the reduction of SIgA, it can weaken the defense against microbial invasion and antiviral activities, leading to repeated respiratory infections. In addition, vitamin A also participates in most of the oxidation processes in the body and promotes immunity, which makes children with respiratory infections more likely to be repeatedly infected, and repeated infections further damage the immune function and form a vicious circle. Vitamin D is a neuroendocrine-immunomodulatory hormone [12], and it mainly affects the proliferation, differentiation, and function of the body’s immune cells. Children with vitamin D deficiency have decreased cellular and humoral immunity, a reduced immune response, reduced antibody production, and an inability to clear antigens, leading to repeated infections. In addition, children with vitamin D deficiency have calcium absorption barriers, and calcium can enhance the ciliary movement of the trachea and bronchus, and enhance the airway clearance function [13]. Consequently, when vitamin D is lacking, the bronchial ciliary movement is weakened, and they are prone to various infections. Vitamin E has a strong antioxidant effect and has an irreplaceable role in the growth and development of the human body. Peripheral blood T lymphocyte percentages and the lymphocyte conversion rate of people with low vitamin E content are significantly lower than those with normal vitamin E content; moreover, vitamin E can improve the stability of vitamin A [8] and affect the body through coordination with vitamin A immune function. Therefore, vitamins A, D, and E are fat-soluble micronutrients, which are essential and are beneficial to children’s development [16-19]. In this study, we explored the correlation between vitamin levels and RRTI children of different ages. Our results found that the serum levels of vitamins A, D, and E in RRTI children aged 0-2, 3-5, and 6-12 years old were significantly lower than those in healthy children, suggesting that the vitamin A, D, and E levels have a certain correlation with the incidence of the disease.
Studies have disclosed that vitamin A is related to the occurrence of multiple human diseases. The growth of respiratory ciliated epithelial tissue is associated with vitamin A, and a deficiency of vitamin A causes the epithelial cell cilia to disappear. It can generate more squamous epithelia, resulting in the loss of glandular cell function. Further, such changes in turn reduce the partial defense function and increase the possibility of pathogen invasion, consequently causing respiratory infections. Meanwhile, the conversion rate of lymphocytes and immunoglobulins is associated with vitamin A levels [20-25].
Thus, it can be seen that a lack of vitamin A will cause the body’s immunity to decrease, contributing to the development of the disease. Vitamin D has to be exposed to hydroxylations twice in the body before exerting its biological effects, and it is involved in the metabolism of phosphorus and calcium and the regulation of the immune system. Vitamin D hydroxylated participates in lymphocyte proliferation, cell differentiation, and cytokine secretion, and plays a critical role in immune diseases. Tocopherol vitamin E is correlated with T cell proliferation and cytokine IL-2 secretions, and it can enhance immune function and anti-inflammation [25-30]. In this study, we found that the vitamin D and E levels in children with RRTIs were significantly lower than the vitamin D and E levels in healthy children, revealing that the vitamin A, D, and E levels have a certain correlation with the clinical incidence of RRTIs. A further correlation analysis showed that vitamins A and D in the serum are negatively correlated with the incidence of RRTIs, and the vitamin E levels are associated with disease, but the correlation was not significant. After 1 year of follow-up, it was found that after reasonable vitamin A, D, and E supplementation, the serum vitamin A, D, and E levels were significantly increased, and the WBC and CRP levels were significantly decreased in the children in the RRTIs group, suggesting that vitamin A, D, and E deficiency and the endoinflammatory response are closely related, but the specific mechanism needs further study.
To summarize, the vitamin A, D, and E levels decrease significantly in children with RRTIs, but only the levels of vitamins A and D are significantly negatively correlated with the incidence of RRTI, suggesting that monitoring the serum vitamin A and D levels contributes to the determination of disease severity. An appropriate amount of vitamins A and D supplementation via the diet or drugs is conducive to the treatment of RRTIs. The limitation of this study is that it did not carefully divide the different vitamin deficiencies of each age group regionally. In the future, epidemiological investigations will be increased and more detailed research will be conducted.
Disclosure of conflict of interest
None.
References
- 1.Imdad A, Herzer K, Mayo-Wilson E, Yakoob MY, Bhutta ZA. Vitamin A supplementation for preventing morbidity and mortality in children from 6 months to 5 years of age. Cochrane Database Syst Rev. 2010;8:CD008524. doi: 10.1002/14651858.CD008524.pub2. [DOI] [PubMed] [Google Scholar]
- 2.Horton S, Blum LS, Diouf M, Ndiaye B, Ndoye F, Niang K, Greig A. Delivering vitamin A supplements to children aged 6-59 months: comparing delivery through campaigns and through routine health services in Senegal. Curr Dev Nutr. 2018;2:nzy006. doi: 10.1093/cdn/nzy006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Hollm-Delgado MG, Piel FB, Weiss DJ, Howes RE, Stuart EA, Hay SI, Black RE. Vitamin A supplements, routine immunization, and the subsequent risk of Plasmodium infection among children under 5 years in sub-Saharan Africa. Elife. 2015;4:e03925. doi: 10.7554/eLife.03925. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Conaway HH, Henning P, Lerner UH. Vitamin a metabolism, action, and role in skeletal homeostasis. Endocr Rev. 2013;34:766–97. doi: 10.1210/er.2012-1071. [DOI] [PubMed] [Google Scholar]
- 5.De-Regil LM, Palacios C, Lombardo LK, Peña-Rosas JP. Vitamin D supplementation for women during pregnancy. Cochrane Database Syst Rev. 2016;14:CD008873. doi: 10.1002/14651858.CD008873.pub3. [DOI] [PubMed] [Google Scholar]
- 6.Tanaka K, Hitsumoto S, Miyake Y, Okubo H, Sasaki S, Miyatake N, Arakawa M. Higher vitamin D intake during pregnancy is associated with reduced risk of dental caries in young Japanese children. Ann Epidemiol. 2015;25:620–5. doi: 10.1016/j.annepidem.2015.03.020. [DOI] [PubMed] [Google Scholar]
- 7.Ciresi A, Giordano C. Vitamin D across growth hormone (GH) disorders: from GH deficiency to GH excess. Growth Horm IGF Res. 2017;33:35–42. doi: 10.1016/j.ghir.2017.02.002. [DOI] [PubMed] [Google Scholar]
- 8.Taylor S, Lopez P, Weckx L, Borja-Tabora C, Ulloa-Gutierrez R, Lazcano-Ponce E, Kerdpanich A, Angel Rodriguez Weber M, Mascareñas de Los Santos A, Tinoco JC, Safadi MA, Lim FS, Hernandez-de Mezerville M, Faingezicht I, Cruz-Valdez A, Feng Y, Li P, Durviaux S, Haars G, Roy-Ghanta S, Vaughn DW, Nolan T. Respiratory viruses and influenza-like illness: epidemiology and outcomes in children aged 6 months to 10 years in a multi-country population sample. J Infect. 2017;74:29–41. doi: 10.1016/j.jinf.2016.09.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Bergman P, Lindh AU, Björkhem-Bergman L, Lindh JD. Vitamin D and respiratory tract infections: a systematic review and meta-analysis of randomized controlled trials. PLoS One. 2013;8:e65835. doi: 10.1371/journal.pone.0065835. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Grant CC, Kaur S, Waymouth E, Mitchell EA, Scragg R, Ekeroma A, Stewart A, Crane J, Trenholme A, Camargo CA Jr. Reduced primary care respiratory infection visits following pregnancy and infancy vitamin D supplementation: a randomised controlled trial. Acta Paediatr. 2015;104:396–404. doi: 10.1111/apa.12819. [DOI] [PubMed] [Google Scholar]
- 11.Glade MJ. Vitamin D: health panacea or false prophet? Nutrition. 2013;29:37–41. doi: 10.1016/j.nut.2012.05.010. [DOI] [PubMed] [Google Scholar]
- 12.Wójcik D, Szalewski L, Pietryka-Michałowska E, Borowicz J, Pels E, Beń-Skowronek I. Vitamin D3 and dental caries in children with growth hormone deficiency. Int J Endocrinol. 2019;2019:2172137. doi: 10.1155/2019/2172137. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Aglipay M, Birken CS, Parkin PC, Loeb MB, Thorpe K, Chen Y, Laupacis A, Mamdani M, Macarthur C, Hoch JS, Mazzulli T, Maguire JL. Effect of high-dose vs standard-dose wintertime vitamin D supplementation on viral upper respiratory tract infections in young healthy children. JAMA. 2017;318:245–254. doi: 10.1001/jama.2017.8708. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Evans HM, Bishop KS. On the existence of a hitherto unrecognized dietary factor essential for reproduction. Science. 2006;56:650–651. doi: 10.1126/science.56.1458.650. [DOI] [PubMed] [Google Scholar]
- 15.Evans HM. The pioneer history of Vitamin E. Vitam Horm. 1962;20:379–387. [Google Scholar]
- 16.Evans HM, Emerson OH, Emerson GA. The isolation from wheat germ oil of an alcohol, a - tocopherol, having the properties of vitamin E. Nutr Rev. 1974;32:80–82. doi: 10.1111/j.1753-4887.1974.tb06280.x. [DOI] [PubMed] [Google Scholar]
- 17.Stone CA Jr, McEvoy CT, Aschner JL, Kirk A, Rosas-Salazar C, Cook-Mills JM, Moore PE, Walsh WF, Hartert TV. Update on vitamin E and its potential role in preventing or treating bronchopulmonary dysplasia. Neonatology. 2018;113:366–378. doi: 10.1159/000487388. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Allan KM, Prabhu N, Craig LC, McNeill G, Kirby B, McLay J, Helms PJ, Ayres JG, Seaton A, Turner SW, Devereux G. Maternal vitamin D and E intakes during pregnancy are associated with asthma in children. Eur Respir J. 2015;45:1027–36. doi: 10.1183/09031936.00102214. [DOI] [PubMed] [Google Scholar]
- 19.Devereux G, Craig L, Seaton A, Turner S. Maternal vitamin D and E intakes in pregnancy and asthma to age 15 years: a cohort study. Pediatr Pulmonol. 2019;54:11–19. doi: 10.1002/ppul.24184. [DOI] [PubMed] [Google Scholar]
- 20.National Institute of Health. Vitamin E - health professional fact sheet. [Online] National Institute of Health. 2016 [Google Scholar]
- 21.Brion LP, Bell EF, Raghuveer TS. Variability in the dose of intravenous vitamin E given to very low birth weight infants. J Perinatol. 2005;25:139–42. doi: 10.1038/sj.jp.7211223. [DOI] [PubMed] [Google Scholar]
- 22.German JB, Dillard CJ. Saturated fats: what dietary intake? Am J Clin Nutr. 2004;80:550–9. doi: 10.1093/ajcn/80.3.550. [DOI] [PubMed] [Google Scholar]
- 23.Esposito S, Rigante D, Principi N. Do children’s upper respiratory tract infections benefit from probiotics? BMC Infect Dis. 2014;14:194. doi: 10.1186/1471-2334-14-194. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1789–1858. doi: 10.1016/S0140-6736(18)32279-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Najada AS, Habashneh MS, Khader M. The frequency of nutritional rickets among hospitalized infants and its relation to respiratory diseases. J Trop Pediatr. 2004;50:364–8. doi: 10.1093/tropej/50.6.364. [DOI] [PubMed] [Google Scholar]
- 26.Mantis NJ, Rol N, Corthésy B. Secretory IgA’s complex roles in immunity and mucosal homeostasis in the gut. Mucosal Immunol. 2011;4:603–11. doi: 10.1038/mi.2011.41. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Hall JA, Grainger JR, Spencer SP, Belkaid Y. The role of retinoic acid in tolerance and immunity. Immunity. 2011;35:13–22. doi: 10.1016/j.immuni.2011.07.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Kim KC, McCracken K, Lee BC, Shin CY, Jo MJ, Lee CJ, Ko KH. Airway goblet cell mucin: its structure and regulation of secretion. Eur Respir J. 1997;10:2644–9. doi: 10.1183/09031936.97.10112644. [DOI] [PubMed] [Google Scholar]
- 29.Kim SW, Hong JS, Ryu SH, Chung WC, Yoon JH, Koo JS. Regulation of mucin gene expression by CREB via a nonclassical retinoic acid signaling pathway. Mol Cell Biol. 2007;27:6933–47. doi: 10.1128/MCB.02385-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Underwood MA, Bevins CL. Defensin-Barbed innate immunity: clinical associations in the pediatric population. Pediatrics. 2010;125:1237–1247. doi: 10.1542/peds.2009-3289. [DOI] [PubMed] [Google Scholar]